Effects of proprotein convertase subtilisin/kexin type 9 and nilotinib plasma concentrations on nilotinib‐induced hypercholesterolaemia in patients with chronic myeloid leukaemia

Abstract

What is known and objective The purpose of this study was to investigate the relationships among nilotinib plasma trough concentration (C0), low‐density lipoprotein (LDL) cholesterol, and PCSK9 plasma concentration in 31 patients with chronic myeloid leukaemia. Methods Plasma concentrations of nilotinib and PCSK9 were measured by high‐performance liquid chromatography and enzyme‐linked immunosorbent assays, respectively. Results and discussion LDL cholesterol concentrations at 1 month after nilotinib treatment were significantly increased compared with those before therapy. The mean C0 (±SD) of nilotinib at 1, 2, and 3 months after nilotinib treatment were 645 ± 516, 902 ± 623, and 951 ± 1088 ng/mL, respectively. Mean PCSK9 concentrations at 3 months after nilotinib treatment were significantly higher than those at the start of therapy (320 vs 257 ng/mL, respectively, P = .019). When the change rate in the PCSK9 concentration induced by nilotinib was classified with a cut‐off value of +40%, the change rate in LDL cholesterol in patients with a change rate in PCSK9 of ≥40% was significantly higher than that in patients with a PCSK9 change rate of <40% (67.1% vs 38.0%, P = .043); however, there were no differences in mean nilotinib C0. What is new and conclusion Nilotinib may lead to hypercholesterolaemia by increasing plasma concentrations of PCSK9 after indirect inhibition of mammalian target of rapamycin (mTOR) complex 1. In addition, certain patients seem to have high sensitivity for nilotinib in a signalling cascade of the PI3K/Akt/mTOR pathway, despite low plasma concentrations of nilotinib. Consequently, nilotinib‐induced hypercholesterolaemia could not be predicted based on the plasma concentration of nilotinib.

Prevalence of cardiovascular risk factors, target organ damage, and subclinical and symptomatic cardiovascular disease in a national population of patients with chronic myeloid leukemia

“…These changes happen early at the beginning of treatment-within the first 12 monthsand are kept during treatment. [34][35][36] Regarding TOD, 8.20% of our patients had LVH while 19.20% had microalbuminuria. A total of 26% of these patients had elevated PWV levels while 32.90% had elevated US-CRP levels.…”

Concentration of low-density lipoproteins (LDL) is significantly reduced after nilotinib discontinuation

“…Nilotinib produces an early increase in the LDL levels, since the first month of the treatment, secondary to the higher concentration of proprotein convertase subtilisin/kexin type 9 (PCSK9), due to the mTORC1 inhibition, among other causes 14 . Besides, it has been observed that these patients present higher concentrations of LDL oxidatively modified (oxLDL) than the patients treated with imatinib and dasatinib, as demonstrated by the KIARO study in a recently published multicenter study 15 .…”

Prevalencia de los factores de riesgo cardiovascular, lesión de órgano diana y enfermedad cardiovascular subclínica y sintomática en una cohorte nacional de pacientes con leucemia mieloide crónica

“…Se ha especulado con que el nilotinib podría, en algunos casos, aumentar las cifras de colesterol vinculado a lipoproteínas de baja densidad (c-LDL) de forma secundaria al incremento en la concentración de la proproteína convertasa subtilisina/kexina tipo 9 (PCSK9), mediado por la inhibición de mTORC1. Estos cambios se producen de forma precoz al inicio del tratamiento, en los primeros 12 meses, y se mantienen durante el tratamiento [34][35][36] .…”